title: RhoA GTPase controls cytokinesis and programmed necrosis of hematopoietic progenitors.
abstract: Hematopoietic progenitor cells (HPCs) are central to hematopoiesis as they provide large numbers of lineage-defined blood cells necessary to sustain blood homeostasis. They are one of the most actively cycling somatic cells, and their precise control is critical for hematopoietic homeostasis. The small GTPase RhoA is an intracellular molecular switch that integrates cytokine, chemokine, and adhesion signals to coordinate multiple context-dependent cellular processes. By using a RhoA conditional knockout mouse model, we show that RhoA deficiency causes a multilineage hematopoietic failure that is associated with defective multipotent HPCs. Interestingly, RhoA(-/-) hematopoietic stem cells retained long-term engraftment potential but failed to produce multipotent HPCs and lineage-defined blood cells. This multilineage hematopoietic failure was rescued by reconstituting wild-type RhoA into the RhoA(-/-) Lin(-)Sca-1(+)c-Kit(+) compartment. Mechanistically, RhoA regulates actomyosin signaling, cytokinesis, and programmed necrosis of the HPCs, and loss of RhoA results in a cytokinesis failure of HPCs manifested by an accumulation of multinucleated cells caused by failed abscission of the cleavage furrow after telophase. Concomitantly, the HPCs show a drastically increased death associated with increased TNF-RIP-mediated necrosis. These results show that RhoA is a critical and specific regulator of multipotent HPCs during cytokinesis and thus essential for multilineage hematopoiesis.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, 2 Molecular and Development Biology Graduate Program, 3 Division of Ophthalmology, and 4 Division of Developmental Biology, Cincinnati Children's Research Foundation, University of Cincinnati, Cincinnati, OH 45229.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Florian
authors.forename: Paritha
authors.initials: P
authors.lastname: Arumugam
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Chen
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
authors.forename: Richard
authors.initials: R
authors.lastname: Lang
authors.forename: Punam
authors.initials: P
authors.lastname: Malik
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D048749:Cytokinesis / Q000187:drug effects; D000080865:Formins; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D054377:Chemokine CXCL12; C491464:Diap1 protein, mouse; D000080865:Formins; D000205:Actomyosin; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein